The innate immune system is a cooperative network of host defenses that utilizes both soluble components and cellular defenses. Central to innate immunerecognition are pattern recognition receptors (PRRs)that recognize pathogen derivatives or altered-self components normallyabsent from the healthy host. Numerousfamilies of PRRs have been identified includingthe well-defined Toll-likeand Nod-like receptors (TLRand NLRs). In addition to these molecules another large family of PRRs are the scavenger receptor family of proteins. Scavenger receptors (SRs) are structurally unrelated receptors that share the ability to bind polyanionic ligands. This simple definition belies the importance of SRsas PRRs - SRsare archetypal multifunctional receptors, often able to bind ligands of both pathogen and self-origin. SRsare found on cells that patrol potential portals of pathogen entry such as endothelial cells and phagocytes, including macrophages, dendriticcells andmicroglia. Different cells express distinct repertoires of PRRincludingSRsprovidingthem with a unique PRR signature, defined by both the cell type and the tissue oforigin. In addition to functioning as phagocytic/endocytic receptors, some SRscan both signal independently and cooperatively with other families of PRRs such as the TLRs to respond to pathogens. Thus, through combinatorialsignaling,SRshelp fine-tunepathogen-specific responses. In addition, SRsare the major class of receptors for modified endogenous ligands providinga link between innate immune activation and sterile inflammatorydiseases. However, despite the importance of SRsin pathogen recognition and the emergence of new roles for these molecules in inflammation, the field of scavenger receptor biologyhas significantly lagged behind that of TLRs and NLRs. Specifically, several essential reagents to study SRsare lackingand hence have limited the study of many of these molecules both in vitro and in vivo. Here we propose to focus on developing scavenger-receptor based reagents. Specifically we propose to develop reagents that 1) will facilitate studies of SRbiology and SR-ligand interactions, 2) inhibitthe function of SRsin ligand uptake and signalingand 3) that will utilizethe SRsexpressed by different immune cells to deliver nanoparticle based reagents to specific subpopulations of cells in vivo. RELEVANCE (See instructions): Immune defense against pathogens is initiated after microbial recognition by pattern recognition receptors. Scavenger receptors (SRs) are an important family of such receptors, involved in protection against diverse pathogens. Understanding the role of SRs in immunity is crucial to advance vaccine development and to generate new therapeutics for biodefense and emerging infectious diseases. We propose to generate a comprehensive panel of reagents to facilitate study of these important innate immune receptors